Preventive and Therapeutic medicament for gastroesophageal reflux disease

ABSTRACT

The compound of the following formula: 
     
       
         
         
             
             
         
       
     
     wherein R 1  and R 2  independently represent a hydrogen atom or a lower alkyl group; A represents a group selected from the group consisting of 1-azabicyclo[3.2.2]nonyl group, 1-azabicyclo[2.2.2]octyl group, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof or a hydrate thereof has both improving effect on enterokinetic functions and suppressing effect on acid secretion, and also is highly safe. Accordingly, the substance is useful as preventive or therapeutic medicament for a gastroesophageal reflux disease.

TECHNICAL FIELD

The present invention relates to a medicament comprisingthieno[3,2-b]pyridinecarboxamide derivative as an active ingredientwhich is useful for preventive and/or therapeutic treatment of agastroesophageal reflux disease.

BACKGROUND ART

Gastroesophageal reflux disease (hereafter referred to as “GERD”) is ageneric term of diseases with various digestive symptoms such aspyrosis, acid regurgitation, obstructed admiration, aphagia,pectoralgia, permeating feeling and the like sensibility caused byreflux in the esophagus and stagnation of gastric contents, duodenaljuice, bile, pancreatic juice and the like. The term covers both ofreflux esophagitis in which erosion and ulcers are endoscopicallyobserved, and esophageal regurgitation-type non-ulcer dyspepsia (NUD) inwhich no abnormality is endoscopically observed.

Examples of causes of GERD include intraesophageal reflux of gastriccontents due to lowered contractibility of the lower esophagealsphincter, reduced resistance of esophageal mucosa to acid and/orpepsin, reduction of esophageal clearance after reflux, prolongation ofgastric evacuation, esophageal hiatus hernia and the like.

For treatment of GERD, administrations of acid secretion depressors suchas a histamine H₂ receptor antagonists and proton pump inhibitors,and/or administrations of agents for improvement of enterokineticfunctions such as cisapride which improve lowered contractibility of thelower esophageal sphincter and prolongation of gastric evacuation havebeen mainly applied.

However, a sole administration of a single histamine H₂ receptorantagonist or agent for improvement of enterokinetic functions sometimesfails to achieve satisfactory therapeutic effect. In addition, althoughthe proton pump inhibitors can achieve high efficacy, their prolongedadministrations have not been approved from a viewpoint of safety, whichmay arise a problem of recurrence. For these reasons, development of amedicament has been desired which can be administered for a prolongedperiod of time, and has a high effectiveness and reduced side effect.

An object of the present invention is to provide a medicament havinghigh efficacy for preventive and/or therapeutic treatment of agastroesophageal reflux disease and reduced side effect.

DISCLOSURE OF THE INVENTION

The inventors of the present invention conducted various researches toachieve the foregoing object. As a result, they found that a particularclass of thieno[3,2-b]pyridinecarboxamide derivatives has both excellentimproving effect on enterokinetic functions and suppressing effect onacid secretion. The present invention was achieved on the basis of thefindings.

The present invention thus provides a preventive or therapeuticmedicament for a gastroesophageal reflux disease which comprises as anactive ingredient a thieno[3,2-b]pyridinecarboxamide derivativerepresented by the following formula (I) or a pharmaceuticallyacceptable salt thereof, or a solvate or a hydrate thereof:

wherein R¹ and R² independently represent a hydrogen atom or a loweralkyl group; A represents a group selected from the group consisting of1-azabicyclo[3.2.2]nonyl group, 1-azabicyclo[2.2.2]octyl group, or anN-oxide thereof.

According to preferred embodiments of the present invention, providedare the aforementioned preventive or therapeutic medicament, wherein R¹and R² independently represent a hydrogen atom or methyl group; theaforementioned preventive or therapeutic medicament, wherein A is1-azabicyclo[2.2.2]oct-3-yl group or an N-oxide thereof; theaforementioned preventive or therapeutic medicament, wherein each of R¹and R² is a hydrogen atom and an absolute configuration of a carbon atomin the group A attached to the carboxamide group is R-configuration; andthe aforementioned preventive or therapeutic medicament, wherein theactive ingredient is in a form of a hydrochloride.

As an active ingredient of the preventive or therapeutic medicament ofthe present invention, one or more of the compounds falling within thethieno[3,2-b]pyridinecarboxamide derivative represented by the aboveformula. In the formula, R¹ and R² independently represents a hydrogenatom or a lower alkyl group. Examples of the lower alkyl group includeC₁-C₆ alkyl groups such as methyl group, ethyl group, n-propyl group,i-propyl group, n-butyl group, sec-butyl group, tert-butyl group and thelike, or preferably C₁-C₄ alkyl groups. Among them, methyl group ispreferred. The compounds wherein each of R¹ and R² is a hydrogen atomare also preferred active ingredients of the medicament of the presentinvention. When R² represents a lower alkyl group, R² may substitute oneither of 2-position or 3-position of thieno[3,2-b]pyridine ring.

In the aforementioned formula (I), A represents 1-azabicyclo[3.2.2]nonylgroup or 1-azabicyclo[2.2.2]octyl group, or a group wherein the nitrogenatom of each of the aforementioned group forms N-oxide. A bond betweenthe group A and the carboxamide group of the compound of the formula (I)is formed by any carbon atom of the group A and the nitrogen atom of thecarboxamide group. Example of the group A include, for example,1-azabicyclo[2.2.2]oct-2-yl group, 1-azabicyclo[2.2.2]oct-3-yl group,1-azabicyclo[2.2.2]oct-4-yl group, 1-azabicyclo[3.2.2]non-2-yl group,1-azabicyclo[3.2.2]non-3-yl group, 1-azabicyclo[3.2.2]non-4-yl group,1-azabicyclo[3.2.2]non-5-yl group, 1-azabicyclo[3.2.2]non-6-yl group,1-azabicyclo[3.2.2]non-7-yl group, and groups corresponding to theirN-oxides.

Stereochemistry of a carbon atom in the group A that binds to thenitrogen atom of the carboxamide group is not particularly limited, andthe atom may be in either R- or S-configuration. As for the group A, aracemate, or a mixture in any ratio of optical isomers may be used. Whenan optically active group A is used, those wherein an absoluteconfiguration of the above carbon atom is R-configuration may preferablybe used.

Among the compounds as active ingredients of the medicament of thepresent invention, examples of particularly preferred compounds includea racemate or any optically active isomers, or their N-oxides of:

-   N-(1-azabicyclo[2.2.2]oct-3-yl)-4,7-dihydro-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[2.2.2]oct-3-yl)-4,7-dihydro-4-methyl-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[2.2.2]oct-3-yl)-4,7-dihydro-4-ethyl-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[2.2.2]oct-3-yl)-4,7-dihydro-2,4-dimethyl-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[2.2.2]oct-3-yl)-4,7-dihydro-3,4-dimethyl-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[2.2.2]oct-3-yl)-4,7-dihydro-4-ethyl-2-methyl-7-oxo-thieno[3,2-b]-pyridine-6-carboxamide;-   N-(1-azabicyclo[2.2.2]oct-2-yl)-4,7-dihydro-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[2.2.2]oct-2-yl)-4,7-dihydro-4-methyl-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[2.2.2]oct-2-yl)-4,7-dihydro-4-ethyl-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[2.2.2]oct-2-yl)-4,7-dihydro-2,4-dimethyl-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[2.2.2]oct-2-yl)-4,7-dihydro-3,4-dimethyl-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[2.2.2]oct-2-yl)-4,7-dihydro-4-ethyl-2-methyl-7-oxo-thieno[3,2-b]-pyridine-6-carboxamide;-   N-(1-azabicyclo[2.2.2]oct-4-yl)-4,7-dihydro-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[2.2.2]oct-4-yl)-4,7-dihydro-4-methyl-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[2.2.2]oct-4-yl)-4,7-dihydro-4-ethyl-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[2.2.2]oct-4-yl)-4,7-dihydro-2,4-dimethyl-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[2.2.2]oct-4-yl)-4,7-dihydro-3,4-dimethyl-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[2.2.2]oct-4-yl)-4,7-dihydro-4-ethyl-2-methyl-7-oxo-thieno[3,2-b]-pyridine-6-carboxamide;-   N-(1-azabicyclo[3.2.2]non-2-yl)-4,7-dihydro-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[3.2.2]non-2-yl)-4,7-dihydro-4-methyl-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[3.2.2]non-2-yl)-4,7-dihydro-4-ethyl-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[3.2.2]non-2-yl)-4,7-dihydro-2,4-dimethyl-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[3.2.2]non-2-yl)-4,7-dihydro-3,4-dimethyl-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[3.2.2]non-2-yl)-4,7-dihydro-4-ethyl-2-methyl-7-oxo-thieno[3,2-b]-pyridine-6-carboxamide;-   N-(1-azabicyclo[3.2.2]non-3-yl)-4,7-dihydro-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[3.2.2]non-4-yl)-4,7-dihydro-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[3.2.2]non-5-yl)-4,7-dihydro-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;-   N-(1-azabicyclo[3.2.2]non-6-yl)-4,7-dihydro-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;    and-   N-(1-azabicyclo[3.2.2]non-7-yl)-4,7-dihydro-7-oxo-thieno[3,2-b]pyridine-6-carboxamide.    However, the active ingredients of the medicaments of the present    invention are not limited to these compounds.

Among them, most preferred compounds areR-(−)-N-(1-azabicyclo[2.2.2]oct-3-yl)-4,7-dihydro-7-oxo-thieno[3,2-b]pyridine-6-carboxamide[also referred to as(R)—N-(3-quinuclidinyl)-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide]or N-oxide thereof. When R¹ represents a hydrogen atom in theaforementioned formula (I), 4,7-dihydro-7-oxo-thieno[3,2-b]pyridine as aheteroaromatic ring moiety may also exist as a tautomer thereof, i.e.,7-hydroxythieno[3,2-b]pyridine. Such tautomers also fall within theactive ingredients of the medicament of the present invention.

Methods for preparation of the aforementioned compounds are described inJapanese Patent Unexamined Publication (KOKAI) No. 5-310747 (EP560348).

As an active ingredient of the medicament of the present invention,pharmaceutically acceptable salts of the aforementioned compounds may beused. Examples of the salts include acid addition salts, quaternaryammonium salts and the like. Examples of the pharmaceutically acceptableacid addition salts include, for example, inorganic acid salts such ashydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates andthe like, and organic acid salts such as oxalates, maleates, fumarates,lactates, malates, citrates, tartrates, benzoates, methanesulfonates andthe like.

Examples of the quaternary ammonium salts include, for example,quaternary ammonium salts with lower alkyl halogenides such as methyliodides, methyl bromides, ethyl iodides, ethyl bromides and the like,those with lower alkyl sulfonates such as methyl methanesulfonates,ethyl methanesulfonates and the like, and those with lower alkylarylsulfonates such as methyl p-toluenesulfonates and the like. Thecompounds represented by the formula (I) or pharmaceutically acceptablesalts thereof may exist as hydrates. These hydrates may be used asactive ingredients of the medicament of the present invention.

Japanese Patent Unexamined Publication (KOKAI) No. 5-310747 disclosesenhancing effect of the aforementioned compound on stomach motility,more specifically, enhancing action on stomach evacuation in male ddymice, enhancing action on constriction of a dog stomach sewed with astrain gauge transducer, and an antagonistic action on a 5-HT₃(serotonin 3) receptor demonstrated by the Bezold-Jarish reflectivetest. However, the publication neither suggests nor teaches a relationbetween the aforementioned compound and acid secretion.

Japanese Patent Unexamined Publication (KOKAI) No. 8-143573 disclosesthat the aforementioned compound promotes transportation of intestinalcontents by stimulating peristalsis of the stomach and small intestine,more specifically, promoting action on constricting motility of thevestibular stomach, duodenum, jejunum, and ileum of a dog, and promotingaction on mouse large intestine transportation, and further a result ofobservation of general conditions of mice indicating the safety of theaforementioned compound. However, the publication neither suggests norteaches a relation between the aforementioned compound and acidsecretion.

It is preferred that a pharmaceutical composition is prepared by addinga pharmaceutically acceptable carrier to the aforementioned compound, apharmaceutically acceptable salt thereof, or a hydrate thereof as anactive ingredient of the medicament of the present invention. As themedicament of the present invention, a substance, per se, that isselected from the group consisting of the alkylenedioxybenzenederivative and a pharmaceutically acceptable salt thereof, and a hydratethereof and a solvate thereof may be administered to a mammal includinghuman. However, it is generally preferable to prepare a pharmaceuticalcomposition comprising one or more of the aforementioned substances asan active ingredient and one or more of pharmaceutical additives andadminister the composition to a patient.

Examples of the pharmaceutical composition include formulations for oraladministration such as tablets, capsules, subtilized granules, powders,pills, troches, sublingual tablets and liquid preparations, andformulations for parenteral administration such as injections,suppositories, ointments, patches and the like.

Tablets and capsules for oral administration are usually provided in aunit dosage form, and can be prepared by adding ordinary pharmaceuticalcarriers such as binders, fillers, diluents, compressing agents,lubricants, disintegrating agents, coloring matters, flavoring agents,and moistening agents. Tablets may be coated according to a well knownmethod, for example, by using an enteric coating agent. For example,fillers such as cellulose, mannitol and lactose; disintegrating agentssuch as starch, polyvinylpyrrolidone, starch derivatives and sodiumstarchglycolate; lubricants such as magnesium stearate; moisteningagents such as sodium laurylsulfate and the like may be used.

Liquid preparations for oral administration can be provided in the formsof, for example, aqueous or oily suspensions, solutions, emulsions,syrups and elixirs, as well as dried formulations that is re-dissolvablebefore use by water or a suitable medium. Those liquid preparations maycontain ordinary additives, for example, suspending agents such assorbitol, syrups, methylcellulose, gelatin, hydroxyethylcellulose,carboxymethylcellulose, aluminum stearate gel and hydrogenated ediblefats; emulsifiers such as lecitin, sorbitan monooleate and gum arabic;non-aqueous media including edible oils such as almond oil, rectifiedcoconut oil, oily esters (e.g., esters of glycerin), propylene glycoland ethyl alcohol; preservatives such as methyl ester, ethyl ester andpropyl ester of p-hydroxybenzoic acid and sorbic acid; and usualflavoring agents and coloring matters as required.

Formulations for oral administration can be manufactured according to amethod well known in the art, for example, by mixing, filling,compressing and the like. In addition, it is also possible to dispersethe active ingredient in a formulation containing a large amount offiller by repetitive mixing. Formulations for parenteral administrationare generally provided as unit dosage form preparations containing thecompound as the active ingredient and a sterilized medium. The solutionfor parenteral administration may generally be prepared by dissolvingthe compound in a medium, subjecting the resulting solution tofiltration for sterilization, filling the solution in vials or ampoules,and sealing the vials or ampoules. It is also possible to freeze thecomposition and fill the result in vials, and then eliminate themoisture in vacuo to improve stability. Parenteral suspensions can beprepared by substantially the same method as that applied to solutionsfor parenteral administration; however, the suspensions can preferablybe manufactured by suspending the active ingredient in a medium, andthen subjecting the result to sterilization by using ethylene oxide orthe like. Furthermore, surface active agents, moistening agents and soforth may also be added so that a uniform dispersion of the activeingredient can be obtained.

Doses of the aforementioned compound as the active ingredient can besuitably decided depending on the purpose of administration, i.e.,therapeutic or preventive treatment, nature of a disease to be treatedor prevented, conditions, body weight, age, sexuality and the like of apatient. In an usual case, an amount of about 0.001 mg to 10 mg per dayfor an adult may be administered orally, or about 0.001 mg to 10 mg maybe administered by intravenous administration. Such doses may bedesirably administered once a day to several times a day as dividedportions.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be more specifically explained by examples.However, the scope of the present invention is not limited to theseexamples. In the following examples,R-(−)-N-(1-azabicyclo[2.2.2]oct-3-yl)-7-hydroxythieno[3,2-b]-pyridine-6-carboxamide(a tautomer of(R)-(−)-N-(1-azabicyclo[2.2.2.]oct-3-yl)-4,7-dihydro-7-oxo-thieno[3,2-b]pyridine-6-carboxamide)hydrochloride (referred to as “test compound”), prepared according tothe method described in Example 2 of Japanese Patent UnexaminedPublication (KOKAI) No. (Hei) 5-31074, was used.

Example 1 Suppressing Action on Gastric Acid Secretion (HistamineStimulation)

An effect on gastric acid secretion by stimulation under awakening wasstudied by using (fundic pouch dog). For preparation of the fundic pouchdog, a mongrel dog after starvation overnight was subjected to sterileventrotomy under anesthesia using sodium pentobarbital (30 mg/kg, i.v.),and a fistula was attached to a part of the corpus ventriculi. Afterrecovery period for two weeks, the dog was fixed to the Pavlov's stand,and gastric juice was collected every 15 minutes for 4 hours underhistamine stimulation (0.2 mg/kg/hr). A volume of each collected gastricjuice was recorded, and the juice was titrated with 0.01N NaOH using pHautomatic measuring apparatus (Radiometer Copenhagen). The testcompound, encapsulated in a gelatin capsule, was orally administered onehour before histamine administration.

Amount of gastric juice secretion (mEq/4 hr) Control 116.1 ± 12.3 Testcompound 3 μg/kg 76.8 ± 7.4 Test compound 10 μg/kg 61.9 ± 5.5 Values areshown as mean ± standard error for 6 samples

Example 2 Suppressing Action on Gastric Acid Secretion (Tetra GastrinStimulation)

Experiment was conducted in a similar manner as Example 1 except thatthe stimulating agent was replaced with tetragastrin (2 μg/kg/hr). Theresults are shown below.

Amount of gastric juice secretion (mEq/4 hr) Control 40.1 ± 3.9 Testcompound 10 μg/kg 26.7 ± 7.8 Test compound 30 μg/kg 12.9 ± 5.3 Valuesare shown as mean ± standard error for 6 samples

The test compound suppressed secretion of gastric juice by histamine andtetragastrin stimulation.

INDUSTRIAL APPLICABILITY

The medicament of the present invention has both improving effect onenterokinetic functions and suppressing effect on acid secretion, and ishighly safe. Accordingly, the medicament is useful for therapeuticand/or preventive treatment of a gastroesophageal reflux disease.

The present application was filed with the claim of priority based onJapanese patent application No. 2000-31542.

1-5. (canceled)
 6. A method for the treatment of gastroesophageal refluxdisease comprising administering to a patient in need thereof atherapeutically effective amount of(R)—N-(1-azabicyclo[2.2.2]oct-3-yl)-4,7-dihydro-7-oxo-thieno[3,2-b]pyridine-6-carboxamideor the tautomer thereof or a pharmaceutically acceptable salt, solvateor hydrate thereof.
 7. The method of claim 6, wherein the administrationis oral.
 8. The method of claim 7, wherein from about 0.001 mg to about10 mg per day is administered.
 9. The method of claim 7, wherein atablet or capsule is administered.
 10. The method of claim 6, whereinthe(R)—N-(1-azabicyclo[2.2.2]oct-3-yl)-4,7-dihydro-7-oxo-thieno[3,2-b]pyridine-6-carboxamideor the tautomer thereof is in the form of a hydrochloride salt.